Back to the Future: Lessons Learned From the 1918 Influenza Pandemic

Abstract

2018 marks the 100-year anniversary of the 1918 influenza pandemic, which killed ~50 million people worldwide. The severity of this pandemic resulted from a complex interplay between viral, host, and societal factors. Here, we review the viral, genetic and immune factors that contributed to the severity of the 1918 pandemic and discuss the implications for modern pandemic preparedness. We address unresolved questions of why the 1918 influenza H1N1 virus was more virulent than other influenza pandemics and why some people survived the 1918 pandemic and others succumbed to the infection. While current studies suggest that viral factors such as haemagglutinin and polymerase gene segments most likely contributed to a potent, dysregulated pro-inflammatory cytokine storm in victims of the pandemic, a shift in case-fatality for the 1918 pandemic toward young adults was most likely associated with the host's immune status. Lack of pre-existing virus-specific and/or cross-reactive antibodies and cellular immunity in children and young adults likely contributed to the high attack rate and rapid spread of the 1918 H1N1 virus. In contrast, lower mortality rate in in the older (>30 years) adult population points toward the beneficial effects of pre-existing cross-reactive immunity. In addition to the role of humoral and cellular immunity, there is a growing body of evidence to suggest that individual genetic differences, especially involving single-nucleotide polymorphisms (SNPs), contribute to differences in the severity of influenza virus infections. Co-infections with bacterial pathogens, and possibly measles and malaria, co-morbidities, malnutrition or obesity are also known to affect the severity of influenza disease, and likely influenced 1918 H1N1 disease severity and outcomes. Additionally, we also discuss the new challenges, such as changing population demographics, antibiotic resistance and climate change, which we will face in the context of any future influenza virus pandemic. In the last decade there has been a dramatic increase in the number of severe influenza virus strains entering the human population from animal reservoirs (including highly pathogenic H7N9 and H5N1 viruses). An understanding of past influenza virus pandemics and the lessons that we have learnt from them has therefore never been more pertinent.

Keywords: 1918; external factors; host factors; influenza; pandemic; prevention; societal factors; viral factors.

Figure 1

Reassortment events of historic pandemic influenza A viruses, adapted from van de Sandt et al. (2015b). Historic serum analysis suggests that the Russian influenza pandemic of 1889–1892 was of the H3Nx subtype and seasonally circulated up to the 1918 influenza pandemic. It remains undefined whether the 1918 H1N1 pandemic virus originated from multiple reassortment events between avian, swine and human influenza viruses, or if it was introduced by a direct zoonotic transmission event of an avian, swine or other influenza virus. The H1N1 virus continued to circulate, causing seasonal epidemics, until 1957 when it reassorted with an avian H2N2 virus. This virus circulated until 1968, when it reassorted again with the avian H3Nx virus, which has caused seasonal epidemics ever since. In 1977 the H1N1 virus was reintroduced in the human population and co-circulated with H3N2 viruses until the influenza pandemic of 2009 when it was replaced by another H1N1 virus which was the result of multiple reassortment events between avian, swine, and human influenza viruses.

Figure 2

Factors that influence the severity and transmissibility of a pandemic influenza virus. The severity and transmissibility of pandemic influenza viruses are the result of a complex interplay of viral, host, and external factors. We have come a long way since 1918 and pandemic preparedness programs have learned from the 1918 and later pandemic outbreaks. Although unlikely, we cannot exclude the possibility that an influenza pandemic with similar severity will repeat itself in the future. However, lessons learned from the 1918 influenza pandemic will ensure that we are better prepared.